Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([Sn](CCCC)(CCCC)CCCC)[CH:9]=[CH:10][C:11]=1[CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:3])[CH3:2].Br[C:31]1[N:32]=[C:33]([N:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:47]([N:44]1[CH2:43][CH2:42][N:41]([C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:40]=[C:31]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14](=[O:16])[CH3:15])=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:7]=3)[N:32]=2)[CH2:46][CH2:45]1)[CH3:48]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(COC(C)=O)c(COC(C)=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(COC(C)=O)c(COC(C)=O)c3)cc3ccccc23)CC1
Yield: 94.4 %

Procedure:
3,4-Bis(acetoxymethyl)tributylstannylbenzene (1.91 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.00 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.14 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (1.36 g) of 1-(4-ethylpiperazin-1-yl)-3-[3,4-bis(acetoxymethyl)phenyl]isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:14]4[C:9]3=[C:10]([CH:11]=[CH:12][CH:13]=4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:39]([O:44]C)(OC)[O:40]C>C1COCC1.C1CCCCC1>[C:28]1([C:15]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]3[C:9]4=[C:10]([C:6]5[CH:5]=[CH:4][CH:3]=[CH:2][C:7]=5[N:8]4[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=4)[CH:11]=[C:12]([B:39]([OH:44])[OH:40])[CH:13]=3)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Brc1cccc2c3cccc4c3n(c12)-c1ccccc1C4(c1ccccc1)c1ccccc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: OB(O)c1cc2c3c(c1)c1ccccc1n3-c1ccccc1C2(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
125.9 g (259 mmol) of bromo-8,8-diphenyl-8H-indolo[3,2,1-de]acridine are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., after 1 h 37 ml of trimethyl borate (336 mmol) are added dropwise, the mixture is warmed to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification.
Reaction SMILES: CC1C=CC(S([CH2:11][N+:12]#[C-:13])(=O)=O)=CC=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O.[Na].O1CC[N:25]=C1>C(O)C>[NH:12]1[CH:13]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[N:25]=[CH:11]1
Reactant: C1=NCCO1
Reactant: O=Cc1ccccn1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Na]
Solvent: CCO
Product: c1ccc(-c2c[nH]cn2)nc1
Temperature: 15 °C

Procedure:
This compound known in the literature was made by an alternative route in analogy to Heterocycles 1994, 39 (1), 139: Tosylmethylisocyamide (TOSMIC) (3.57 g) was suspended in ethanol (50 ml) and 2-picolinealdehyde (2.0 g) was added. Sodium cyamide (92 mg) was added in one portion at 15° C. and the mixture was allowed to stir—the internal temperature rose to 26° C. and a clear solution was obtained. The mixture was cooled again to 15° C. and the intermediate oxazoline derivative precipitated. The suspension was filtered and the solid intermediate washed with ether/hexanes 1:1 and dried in vacuo (yield: 4.77 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C=O.O.[C:12]([OH:15])(=[O:14])[CH3:13].N(CC(O)=O)CC(O)=O>COCCOC>[C:1]([N:4]([CH2:13][C:12]([OH:15])=[O:14])[CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)NCC(=O)O
Agent: C=O
Agent: O=C(O)CNCC(=O)O
Solvent: COCCOC
Solvent: O
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 110 °C
Yield: 87 %

Procedure:
A 300 mL autoclave was charged with N-acetylglycine (XVIII)(23.4 g, 0.20 mole), 95% paraformaldehyde (6.8 g, 0.22 mole), water (6.5 g, 0.36 mole), acetic acid (16.8 g, 0.28 mole), DME (90 mL), and Co2(CO)8 (2.01 g, 0.006 mole) and pressurized to 1500 psi (10,345 kPa) CO:H2 (95:5) at 25° C. This mixture was heated to 110° C. for 30 min. HPLC analysis of this stream gave an 87% yield of (XVI), 1.0% (XIV), and 10% unreacted (XVIII).
Reaction SMILES: [NH2-].[Li+].[CH3:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]([O:18]CC)(=O)[CH2:13][CH2:14][CH2:15][CH3:16].Cl.[C:22](OC)(C)(C)[CH3:23]>>[CH3:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4](=[O:11])[CH2:3][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:22][CH3:23]
Reactant: CCCCC(=O)OCC
Reactant: CCCCCCC(C)=O
Reactant: COC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [NH2-]
Product: CCCCCCC(=O)CC(=O)CCCCCC
Reaction time: 1 h

Procedure:
Lithium amide (12.4 g, 498 mmol) was dissolved in 130 mL of methyl t-butyl ether (MTBE), and a solution of 32.4 g (253 mmol) of octan-2-one in MTBE (67 mL) was dropped under a nitrogen atmosphere at 35° C. and the mixture was stirred for 1 hour. Then, into this was dropped a solution of 80.0 g (506 mmol) of ethyl pentanoate in MTBE (67 mL), and the mixture was stirred at 35° C. for 4.5 hours. After cooling, the resultant mixed liquid was added into concentrated hydrochloric acid containing ice added, and the oil phase was extracted and died over sodium sulfate, then, concentrated. For purification of the resultant concentrate, a copper acetate aqueous solution was added to cause crystallization of a copper complex of the concentrate, which was dissolved in MTBE and mixed with a sulfuric acid aqueous solution and the mixture was returned to the concentrate, and the oil phase was extracted and dried over sodium sulfate and concentrated, to obtain 36.3 g (151 mmol) of pentadecane-7,9-dione.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4([C:22]([OH:24])=O)[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:25]=1.C(Cl)(=O)C(Cl)=O.[NH2:34][CH2:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][N:40]=[CH:39]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C>[N:38]1([CH2:37][CH2:36][CH2:35][NH:34][C:22]([C:19]2([CH2:18][CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:10]4[C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:27])[F:26])=[CH:25][C:7]=5[S:8][CH:9]=4)[CH2:12][CH2:13]3)[CH2:20][CH2:21]2)=[O:24])[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)C1(CCN2CCN(c3csc4cc(C(F)(F)F)ccc34)CC2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCn1ccnc1)C1(CCN2CCN(c3csc4cc(C(F)(F)F)ccc34)CC2)CC1
Yield: 38 %

Procedure:
A suspension of 0.17 g (0.39 mmol) of 1-{2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-ethyl}-cyclopropanecarboxylic acid in 10 mL dichloromethane under nitrogen was treated with 1 mL of oxalyl chloride followed by 3 drops of DMF. After 2 hours the reaction was concentrated to a slurry, diluted with 10 mL DMF and treated with 0.10 g (0.78 mmol) of 1-(3-aminopropyl)imidazole followed by 0.12 g (1.2 mmol) of triethylamine. After 12 hours the reaction was poured into aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to deliver an oil. Chromatographic purification gave 0.075 g (38%) of the desired final product as an oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11](C)[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[ClH:26]>C1COCC1.O1CCOCC1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[NH:11][C:10](=[O:25])[C:9]=2[Cl:26])[CH2:3]1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Reactant: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)c(Cl)c(=O)[nH]c1=O

Procedure:
Compound 4 (100 mg) in THF (2 mL) was treated with 4M HCl in dioxane (1 mL) at RT for 1 h, concentrated, and then purified by LC-MS to give the title compound. 1H-NMR (400 MHz, DMSO-D6): 8 ppm 12.0 (s, 1H), 7.88 (d, J=7.6 Hz, 1 H), 7.68 (t, J=7.7 Hz, 1 H), 7.49 (t, J=7.7 Hz, 1 H), 7.36 (d, J=7.8 Hz, 1 H), 5.09-5.21 (m, 2 H), 3.17 (m, 2 H), 2.96 (t, J=11.1 Hz, 1 H), 2.86 (d, J=10.6 Hz, 1 H), 2.65 (m, 1 H), 1.90 (d, J=11.6 Hz, 1 H), 1.57 (d, J=13.1 Hz, 1 H), 1.19-1.31 (m, 1 H), 1.03-1.15 (m, 1 H). MS (ES) [m+H] calc'd for C17H19ClN5O2, 360.1; found, 360.1.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH2:20]([C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])=[C:25]([C:27](O)=[O:28])[N:26]=1)C>>[CH3:20][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])=[C:25]([C:27]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:28])[N:26]=1
Reactant: CCc1nc(C(=O)O)c(-c2ccccc2C)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccccc2C)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-M ethyl-5-o-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.31 min; [M+H]+=492.1.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)[NH2:3].[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>CCO>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:2]([C:4]2[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][CH:5]=2)[N:3]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: Cc1ccc(NN)cn1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cn1
Yield: 71 %

Procedure:
A mixture of 5-hydrazinyl-2-methylpyridine hydrochloride from Example B27 (5.0 g, 31.4 mmol) and 4,4-dimethyl-3-oxopentanenitrile (8.3 g, 66.3 mmol) in EtOH (50 mL) was heated at reflux overnight. The reaction was concentrated and the residue was dissolved in EtOAc and neutralized with saturated Na2CO3 solution. The organic layer was dried (Na2SO4), concentrated in vacuo and purified by column chromatography to yield 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-amine (5.2 g, 71% yield). 1HNMR (400 MHz, CDCl3) δ 8.72 (s, 1 H), 7.81 (dd, J=8.0, 2.4 Hz, 1 H), 7.23 (d, J=8.4 Hz, 1 H), 5.54 (s, 1 H), 3.71 (br s, 1 H), 2.58 (s, 3 H), 1.29 (s, 9 H); MS (ESI) m/z: 231.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@@:19]1([CH:34]=[O:35])[CH2:31][CH2:32][CH3:33])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@:19]1([CH2:31][CH2:32][CH3:33])[CH:34]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[OH:35])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCC[C@]1(C=O)CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reactant: Clc1ccc([Mg]Br)cc1Cl
Product: CCC[C@]1(C(O)c2ccc(Cl)c(Cl)c2)CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C

Procedure:
(R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-propyl-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared by reaction of 3,4-dichlorophenyl magnesium bromide with (R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester following the procedure of step 1 of Example 11.
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:8](=[O:9])[CH2:7][CH:6]([N:5]1[C:1](=[O:26])[C:2]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:3]2[C:4]1=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reactant: NCc1ccccc1
Product: COc1ccc(C(CC(=O)NCc2ccccc2)N2C(=O)c3ccccc3C2=O)cc1OC
Yield: 92 %

Procedure:
The procedure of Example 46 is utilized starting with 3-phthalimido-3-(3,4'-dimethoxyphenyl)propionic acid and benzylamine (1.0 equiv) to afford 2.45 g (92%) of 3-phthalimido-3-(3',4'-dimethoxyphenyl)propionic benzylamide as white powder: mp 208.4°-209.8° C.; 1H NMR (DMSO-d6, 250 MHz) δ 8.60 (t, 1 H, J=6 Hz), 7.78-7.92 (m, 4 H), 6.85-7.20 (m, 8 H), 5.73 (t, 1 H, J=8 Hz), 4.10-4.30 (m, 2 H), 3.73 (s, 3 H), 3.72 (s, 3 H), 3.20-3.45 (m, 2 H); 13C NMR (DMSO-d6) δ 169.1, 167.7, 148.5, 148.3, 139.2, 134.5, 131.4, 131.2, 127.9, 126.7, 123.1, 119.5, 111.5, 111.2, 101.9, 55.4, 55.37, 50.6, 41.7, 37.4; Anal. Calcd. for C26H24N2O5. Theoretical: C, 70.26; H, 5.44; N, 6.30. Found: C, 70.12; H, 5.53; N, 6.25.
Reaction SMILES: [Cl:1]C1C=C(Cl)C=CC=1COC1C=CC(CCO)=CC=1.S(Cl)(Cl)=O.Cl[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[CH:29][CH:28]=1.[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1.[Na].N1C=CN=C1.[H-].[Na+]>CN(C)C=O>[ClH:1].[Cl:42][C:36]1[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:35]=1[CH2:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][N:43]2[CH:47]=[CH:46][N:45]=[CH:44]2)=[CH:28][CH:29]=1
Reactant: c1c[nH]cn1
Reactant: OCCc1ccc(OCc2ccc(Cl)cc2Cl)cc1
Reactant: ClCCc1ccc(OCc2ccc(Cl)cc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cl
Product: Clc1ccc(COc2ccc(CCn3ccnc3)cc2)c(Cl)c1
Reaction time: 6 h

Procedure:
2.8 g. of sodium hydroxide in 10 ml. of water and 13.6 g. of 2,4-dichlorobenzyl alcohol are added to 8 g. of 4-hydroxyphenethyl alcohol in 80 ml. of ethanol. After refluxing the solution for 1.5 hours, the mixture is acidified with dilute sulfuric acid and extracted with methylene chloride. Drying and evaporation of the solvent yields the crude product at 100°-130° (air bath temperature)//0.02 torr by distillation with the use of a bulb tube. From cyclohexane, 14.5 g. of 4-(2,4-dichlorobenzyloxy)-phenethyl alcohol is obtained, m.p. 55°. The alcohol is converted, by 10 minutes of heating with thionyl chloride, into the [4-(β-chloroethyl)-phenyl]-(2,4-dichlorobenzyl)-ether and added to a solution of sodium imidazole, obtained by reacting 2 g. of imidazole with 1.04 g. of 80% strength sodium hydride - oil suspension in 30 ml. of dimethylformamide; the mixture is agitated for 6 hours at 100°-120° . The product is worked up as indicated in Example 56.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:9]([O:11][C:12](=[O:16])/[CH:13]=[CH:14]\I)[CH3:10]>>[CH2:9]([O:11][C:12](=[O:16])[CH:13]=[CH:14][C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:10]
Reactant: CCOC(=O)/C=C\I
Reactant: C#Cc1cccnc1
Product: CCOC(=O)C=CC#Cc1cccnc1

Procedure:
The modified procedure was used to convert 3-Ethynyl-pyridine and (Z)-ethyl-3-iodoacrylate to the title product in 12 hours. Purification by flash chromatography (30% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (200 mg, 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.57-8.55 (dd, J=4.9, 1.5, 1H), 7.82-7.79 (td, J=7.8, 1.8, 1H), 7.29-7.26 (m, 1H), 6.38-6.35 (d, J=11.4, 1H), 6.21-6.18 (d, J=11.4, 1H), 4.29-4.23 (q, J=7.1, 2H), 1.34-1.31 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.32, 152.25, 149.13, 138.58, 129.22, 122.86, 121.80, 119.68, 96.97, 89.03, 60.34, 14.08. Anal. Calcd. for C12H11NO2: C, 71.63; H, 5.51; N, 6.96; Found C, 71.77; H, 5.64; N, 6.73.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][S:11][C:12]1[CH2:18][CH:17]2[N:14]([C:15](=[O:21])[CH:16]2[CH2:19][CH3:20])[C:13]=1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23].[C:35](Cl)(=[O:37])[CH3:36]>ClCCl.C1C=CC=CC=1>[C:35]([O:8][CH2:9][CH2:10][S:11][C:12]1[CH2:18][CH:17]2[N:14]([C:15](=[O:21])[CH:16]2[CH2:19][CH3:20])[C:13]=1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCO)CC12
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCOC(C)=O)CC12

Procedure:
Triethylamine (13.3 microliters) was added to a solution in 2 ml of dichloromethane of 3.75 mg of the p-nitrobenzyl 3-(2-hydroxyethylthio)-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate obtained in Example 44. Then, 6.8 microliters of acetyl chloride was added dropwise to the resulting solution at -10° C. with stirring. At the same temperature, the mixture was stirred for 10 minutes. The reaction mixture was diluted with 10 ml of benzene, and washed three times with 5 ml of a 0.1 M phosphate buffer (pH6.8). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to afford a yellow oily product.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2([CH3:17])[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].C1COCC1.O>C(O)C>[CH3:17][C:14]1([C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:13])[CH2:15][CH2:16]1
Reactant: CCOC(=O)C1CCN(C(=O)C2(C)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
Yield: 85.7 %

Procedure:
1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (6.34 g, 26.5 mmol) and LiOH (1.67 g, 39.7 mmol) were stirred in a mixture of ethanol (30 mL), THF (30 mL) and water (15 mL) for 90 min at ambient temperature. After evaporation of the volatiles the residue was taken up in dichloro methane and extracted with 1N HCl. The organic phase was dried over sodium sulfate, filtered and evaporated to yield the title product (4.8 g, 86%) as colorless solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)=O.O.[C:17](=[S:20])([S-:19])[NH2:18].[NH4+]>C(O)C>[SH:20][C:17]1[S:19][CH:2]=[C:3]([C:5]2[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=2)[N:18]=1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2csc(S)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a mixture of ethyl 4-(bromoacetyl)benzoate (2 g), water (15 ml) and ethanol (14 ml) was added ammonium dithiocarbamate (813 mg) under stirring at room temperature. The stirring was continued for 1 hour at the same temperature and the resulting crystal was collected by filtration. The crystal was added to a mixture of water (15 ml) and ethanol (15 ml), and the mixture was refluxed for 1.5 hours under stirring. The stirring was continued for 30 minutes at 10° C. to give crystal, which were collected by filtration and dried, to give ethyl 4-(2-mercaptothiazol-4-yl)benzoate (1.15 g).
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=O.[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30]CO[CH2:27][CH2:26]4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.N[C:43]1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=[CH:45][N:44]=1>>[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:26][CH2:27][N:44]([CH3:45])[CH2:43][CH2:30]4)=[CH:20][C:19]=3[O:5][CH3:3])[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1cc(CN2CCN(C)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 18 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-methoxy-4-(4-methyl-piperazin-1-ylmethyl)-benzaldehyde bis trifluoroacetate were reacted to produce the title compound (18%). 1H NMR (d-chloroform): 10.74 (s, 1H), 8.34 (d, J=7 Hz, 1H), 8.03 (s, 1H), 7.12 (m, 2H), 6.37 (m, 3H), 5.55 (d, J=8 Hz, 1H), 5.20 (t, J=7 Hz, 1H), 5.14 (br s, 1H), 4.08 (s, 3H), 3.58 (s, 2H), 3.18 (s, 1H), 2.91 (s, 1H), 2.88 (d, J=7 Hz, 1H), 2.52 (m, 4H), 2.36 (m, 1H), 2.33 (s, 3H), 1.74 (m, 4H), 1.29 (m, 1H). MS: 522.2 (M+H). HPLC retention time: 1.71 minutes (G Method).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[Na+].[CH3:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14]>CC(OC)(C)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:13](=[O:14])[C:12]([CH3:17])([CH3:16])[CH3:11]
Reactant: Nc1ccccc1Cl
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC(C)(C)C(=O)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 2-chloroaniline 46 (200 mL, 1.9 mol) in MTBE (950 mL) in an ice-water bath was added 25 wt % NaOH (480 g, 3 mol). Trimethylacetyl chloride (248.5 mL, 2.02 mol) was then added dropwise and the reaction was stirred overnight at rt. The organic layer was separated, washed with brine (1.0 L) and water (1.0 L), dried over sodium sulfate, and concentrated in vacuo to give 47 (390 g, 97%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>S(Cl)(Cl)=O>[F:20][C:15]1[C:14]2[S:13][CH2:12][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:11])[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C(CSc1ccccc1F)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: O=C1c2cccc(F)c2SCC1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
The acid from Step C (4.5 g, 15 mmole) was dissolved in 30 ml of thionyl chloride and refluxed for four hours. After cooling the thionyl chloride was concentrated and the residue taken up in carbon tetrachloride. The carbon tetrachloride was concentrated and the residue was taken up in 30 ml of dichloroethane. To the dichloroethane solution being cooled in an ice bath, was added aluminum trichloride (total of 2.1 g, 16 mmole) in three portions every 15 min. After stirring the black solution for an additional 30 min at 0° C., a 5% aqueous HCl solution was added. The aqueous phase was separated and extracted twice with methylene chloride. The organic phases were combined, dried (MgSO4), and concentrated to give the crude product as a yellow oil (3.4 g, 82% yield).